Abstract 17315: Specific and Increased Expression of Thrombin Receptor PAR1 in Pulmonary Artery Plays a Key Role in the Pathogenesis of Monocrotaline-induced Pulmonary Hypertension in Rats
Background: The prognosis of pulmonary arterial hypertension (PAH) still remains poor. Identification of therapeutic targets that play not only a key role but also a specific role in the pathogenesis of PAH will be useful for improving the prognosis. In contrast to the systemic artery, the pulmonary artery (PA) has a unique property regarding the vascular effects of thrombin receptor PAR1, which induces vasoconstriction and vascular remodeling. We addressed the hypothesis that PAR1 plays a key and specific role in the pathogenesis of PAH.
Methods and Results: Real-time PCR analysis revealed that the level of PAR1 mRNA in PA of the normal male SD rats (Normal) was more than 2 fold higher than that seen in any of the systemic arteries examined, including common carotid, femoral, supra-mesenteric and renal arteries (n=4-6, p<0.05). The expression of PAR1 mRNA was up-regulated in the monocrotaline-induced PAH model (MCT), 3 weeks after subcutaneous injection of 60 mg/kg monocrotaline (n=6, p<0.01). In the perfused lung preparations isolated from Normal, a bolus injection of 300 nmol PAR1-agonist peptide induced a modest increase in PA pressure (0.33 mmHg, n=9), while it induced a significantly augmented increase (11.3 mmHg, n=6, p<0.01) in MCT. The oral administration of 30 mg/kg/day PAR1 antagonist, atopaxar, starting from day 0 (prevention protocol; Atp-P) and day 14 (treatment protocol; Atp-T) after monocrotaline injection, prevented the increase in pulmonary vascular resistance (PVR, a ratio of RV systolic pressure to cardiac output; Atp-P: 0.68±0.09 mmHg•min/mL, n=8, p<0.01, Atp-T: 0.89±0.11 mmHg•min/mL, n=10, p<0.05) and development of RV hypertrophy (RVH, a mass ratio of RV to LV+septum; Atp-P: 0.37±0.02, n=10, p<0.01, Atp-T: 0.40±0.03, n=12, p<0.05), compared to those seen in MCT (PVR: 1.34±0.14 mmHg•min/mL, n=10, RVH: 0.49±0.02, n=15). Atopaxar had no effect on the systemic blood pressure. The survival of MCT rats was significantly prolonged in Atp-P and Atp-T.
Conclusion: PAR1 is specifically expressed in PA under physiological condition. The increased expression and function of PAR1 plays a key role in the pathogenesis of PAH. Inhibition of PAR1 is therefore a potentially effective therapeutic strategy specifically targeting pathology of PAH.
Author Disclosures: Y. Kuwabara: None. M. Tanaka: None. K. Abe: None. M. Hirano: None. Y. Hirooka: None. K. Sunagawa: None. K. Hirano: None.
- © 2016 by American Heart Association, Inc.